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ATF3 Protects against Renal Ischemia-Reperfusion Injury

Takumi Yoshida^*,, Hidekazu Sugiura^*, Michihiro Mitobe^*, Ken Tsuchiya^*, Satsuki Shirota^*, Sayoko Nishimura^*, Shunji Shiohira^*, Hiroshi Ito, Kiyoshi Nobori, Steven R. Gullans^||, Takashi Akiba^*, and Kosaku Nitta^*

^* Department of Medicine IV and Department of Blood Purification, Tokyo Women's Medical University, Tokyo, Japan; Division of Cardiovascular Medicine, Akita University School of Medicine Akita, Japan; Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan; and ^|| Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts

Correspondence: Dr. Takumi Yoshida, Department of Internal Medicine IV, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-city, Tokyo, Japan 162-8666. Phone: +81-3-3353-8111, ext. 36412; Fax: +81-3-3356-0293; E-mail: tyoshida{at}kc.twmu.ac.jp

Received for publication November 4, 2005. Accepted for publication August 3, 2007.

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H₂O₂) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21^WAF1/CiP1 (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H₂O₂ rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H₂O₂-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673